人附睾蛋白4（human epididymis protein 4, HE4）是一种新的卵巢癌肿瘤标志物， 报道HE4与卵巢癌化疗耐药相关，但机制不详。项目组前期研究证实：1.HE4与AnxA2结合增加卵巢癌侵袭和转移能力，Lewis y抗原与HE4共表达增加上述能力；2.HE4上调整合素 β1的表达，且两蛋白存在相互作用；3.整合素α5β1岩藻糖基化（主要为Lewis y）增强卵巢癌细胞粘附耐药。结合国际上其他最新研究（AnxA2调节整合素 β1内吞与膜表达调控细胞的粘附与运动，并活化FAK、NF-κB等通路），我们推测：HE4与整合素 β1通过特定蛋白位点相互作用增强卵巢癌细胞粘附耐药，HE4岩藻糖糖基化进一步增强上述作用，并通过活化FAK/Akt/NF-κB起作用。本项目成功开展将进一步阐明卵巢癌耐药机制，对卵巢癌的临床治疗及靶向药物的开发提供理论基础。

Human epididymis protein 4 (HE4) is a kind of new ovarian cancer tumor markers, it is reported that HE4 associated with ovarian cancer chemotherapy drug resistance, but the mechanism is unknown. Our project team prophase research confirmed: 1. The binding interaction between HE4 and annexin II promotes ovarian cancer cell invasion and metastasis, ANXA2 contains Lewis y antigen enhance the ability. 2. HE4 can increase the expression of integrinβ1, and the two proteins interact with each other; 3. The integrin α5β1 fucosylation-modified (mainly Lewis y) enhance ovarian cancer cell adhesion resistance. Combinated with other recent international research (Annexin A2 regulates β1 integrin internalization and intestinal epithelial cell migration, activates FAK、NF-κB pathway ), we hypothesize that: HE4-integrinβ1 exist as the complex by specific protein site, which mediate ovarian cancer cell adhesion resistance through activating of FAK/Akt/NF-κB, HE4 fucosylation-modified enhance the effect. The project will further clarify the mechanism of ovarian cancer drug resistance, which offers the theoretical basis for the clinical treatment of ovarian cancer and the development of targeted drugs.